Abstract: With the development of the research on innovative drugs in our country, first-in-class drugs are becoming a main goal for both pharmaceutical companies and scientific institutions. Discovery of first-in-class drugs require amounts of basic research, a massive investment and novel methods, acting as a beacon for the new drug development. In 2020, FDA totally approved 53 novel drugs with 38 small molecules, which still accounting for a major component. Among them, many first-in-class drugs are important including a first EZH2 inhibitor (tazemetostat) for the treatment of epithelioid sarcoma, a first attachment inhibitor (fostemsavir) with novel mechanism for the treatment of HIV, a first farnesyltransferase inhibitor (lonafarnib) for the treatment of Hutchinson-Gilford progeria syndrome (HGPS) and a first MC₄ receptor agonist for the treatment of rare genetic diseases of obesity, etc. The research procedures of the above drugs are representative with new ideas. In this review, we outline 3 of the first-in-class drugs to discuss the research background, discovery and development process as well as the therapeutic potentials to provide methods and ideas for the further drug development.